Cytokine Profiling of Amniotic Fluid from Congenital Cytomegalovirus Infection

Nicolas Bourgon, Wendy Fitzgerald, Hugues Aschard, Jean-François Magny, Tiffany Guilleminot, Julien Stirnemann, Roberto Romero, Yves Ville, Leonid Margolis, Marianne Leruez-Ville, Nicolas Bourgon, Wendy Fitzgerald, Hugues Aschard, Jean-François Magny, Tiffany Guilleminot, Julien Stirnemann, Roberto Romero, Yves Ville, Leonid Margolis, Marianne Leruez-Ville

Abstract

Background: Congenital cytomegalovirus (cCMV) infection is frequent and potentially severe. The immunobiology of cCMV infection is poorly understood, involving cytokines that could be carried within or on the surface of extracellular vesicles (EV). We investigated intra-amniotic cytokines, mediated or not by EV, in cCMV infection.

Methods: Forty infected fetuses following early maternal primary infection and forty negative controls were included. Infected fetuses were classified according to severity at birth: asymptomatic, moderately or severely symptomatic. Following the capture of EV in amniotic fluid (AF), the concentrations of 38 cytokines were quantified. The association with infection and its severity was determined using univariate and multivariate analysis. A prediction analysis based on principal component analysis was conducted.

Results: cCMV infection was nominally associated with an increase in six cytokines, mainly soluble (IP-10, IL-18, ITAC, and TRAIL). EV-associated IP-10 was also increased in cases of fetal infection. Severity of fetal infection was nominally associated with an increase in twelve cytokines, including five also associated with fetal infection. A pattern of specific increase in six proteins fitted severely symptomatic infection, including IL-18soluble, TRAILsoluble, CRPsoluble, TRAILsurface, MIGinternal, and RANTESinternal.

Conclusion: Fetal infection and its severity are associated with an increase in pro-inflammatory cytokines involved in Th1 immune response.

Trial registration: ClinicalTrials.gov NCT03090841 NCT01651585.

Keywords: amniotic fluid; congenital cytomegalovirus infection; cytokines; extracellular vesicles.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Concentrations of relevant cytokines according to fetal infection. Boxplots represent variations in cytokines’ concentrations (median). UF: uninfected fetuses, IF: infected fetuses.
Figure 2
Figure 2
Concentrations of relevant cytokines according to symptomatic state at birth and severity. Boxplots representing represent variations in cytokines’ concentrations (median). UF: unifected fetuses, AIF: asymptomatic infected fetuses, SNSIF: symptomatic and non-severe infected fetuses, SSIF: symptomatic and severe infected fetuses.
Figure 2
Figure 2
Concentrations of relevant cytokines according to symptomatic state at birth and severity. Boxplots representing represent variations in cytokines’ concentrations (median). UF: unifected fetuses, AIF: asymptomatic infected fetuses, SNSIF: symptomatic and non-severe infected fetuses, SSIF: symptomatic and severe infected fetuses.
Figure 3
Figure 3
Prediction accuracy of fetal infection (a) and of severity (b).
Figure 4
Figure 4
Immunobiology of cCMV: focus on cytokines identified in this study and interactions with infected and immune cells. NKC: natural-killer cell, MP: macrophage, Lc Th1: T-cell involved in Th1 immune response, Lc Th2: T-cell involved in Th2 immune response, DC: dendritic cell, TLR: Toll-like receptor, PAMPS/DAMPs: pathogen-associated molecular patterns/damage-associated molecular patterns.

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